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Medical Molecular Biology

Abstract

Histone deacetylases (HDACs) are a class of proteins whose function alters the state of the chromatin via the removal of acetyl groups from histones. Sirtuins compose class III NAD+-dependent deacetylases that have recently been implicated in a wide number of cellular functions. There are seven sirtuin genes (SIRT1-SIRT7) that have been identified in humans. Sirt6 specifically has been shown to be localized to the nucleus and be involved in a number of functions including DNA damage repair mechanisms and increased genomic stability. In Tetrahymena thermophila, four homologs (THD8, THD9, THD11 and THD12) of the SIRT6 gene were identified through bioinformatics. The goal of this research is to elucidate any possible involvement of these four histone deacetylases in the T. thermophila response mechanisms to genotoxic stress and determine if they play a role in the DNA repair mechanisms. Expression of the genes was shown to be altered following exposure to H2O2 and MMS. Localization studies using fluorescently tagged versions of the target genes revealed that THD11 localized to the nucleus following exposure to MMS, while THD8, THD9, and THD12 showed no such localization. Using Tetrahymena strains with altered expression of each protein indicated that increased levels of THD11 provide a protective effect from oxidative damage. These findings indicate that of the four homologs, THD11 appears to be responsible for the role in DNA repair mechanisms seen in SIRT6 in humans.